Central nicotinic receptor agonists ABT-418, ABT-089, and (-)-nicotine reduce distractibility in adult monkeys

Increased distractibility is associated with both Alzheimer's disease and attention deficit disorder. The present study examined the effects of (-)-nicotine and the novel central nicotinic receptor (nAChR) agonists ABT-418 [(S)-3-methyl-2-pyrrolidinyl)isoxazole] and ABT-089 [2-methyl-3-(2-(S)-pyrrolindinylmethoxy)pyridine dihydrochloride] on the delayed recall accuracy of adult monkeys exposed to distracting stimuli. Unpredictable exposure to a random visual array produced marked decrements in recall accuracy on trials with the shortest delay intervals, reducing the accuracy on these trials by 23.4%. Intramuscular (IM) administration of (-)-nicotine, in doses of 5.4-43.3 nmol/kg, attenuated the effect of the distracter, but did not completely prevent it. Both ABT-418 (2.0-16.2 nmol/kg, IM) and ABT-089 (16.4-32.8 nmol/kg, IM) prevented distractibility, producing increases of 7.5-25.0% in accuracy on trials disrupted by distracter exposure. Further, both compounds also improved accuracy on trials during which distracters were not presented, an effect which was not observed after (-)-nicotine administration. Nicotinic-mediated side effects were not observed following administration of any compound. Thus, nAChR stimulation reduces distractibility in adult monkeys and may, therefore, represent a target for the pharmacologic treatment of disorders associated with susceptibility to distraction. ABT-418 and ABT-089 appear to be particularly useful in this regard, a likely result of their selective agonist activity at nAChRs expressed in the brain.